We determined that HIV gp120 binds to an activated form of &#945;4&#946. Because &#945;4&#946 is the principal integrin involved in lymphocyte homing to the lamina propria of gut associated lymphoid tissue (GALT), and HIV-infected CD4 T-cells preferentially localize to lymphoid tissues, particularly GALT, our finding suggests that a direct interaction between HIV gp120 and &#945;4&#946 may be necessary for preferential establishment and/or maintenance of HIV replication in GALT. The binding of gp120 to &#945;4&#946 is mediated by an LDV peptide sequence in the V2 loop that reiterates a structurally homologous binding motif present on MadCAM-1, VCAM-1 and fibronectin, the natural ligands for &#945;4&#946. Removal of this sequence in the HIV envelope abrogates binding to &#945;4&#946 integrin. A prototypical &#945;4&#946 peptide antagonist based on the LDV sequence abrogates binding to gp120. Thus, HIV has acquired, through molecular mimicry, a mechanism to bind to the integrin receptor principally involved in directing lymphocytes to the lamina propria of the gut, the primary site of HIV replication. On CD4+ T cells, gp120 engagement of &#945;4&#946 results in a rapid activation of LFA-1, the central integrin involved in the establishment of virological synapses. Activation of LFA-1 is known to increase HIV replication. Both activated and resting CD4+ T cells in mucosal tissues play important roles in the earliest phases of infection after sexual transmission of HIV-1, a process that is inefficient. We find that &#945;4&#946;7high CD4+ T cells are more susceptible to productive infection than &#945;4&#946;7low-neg CD4+ T cells, in part, because this cellular subset is enriched with metabolically active CD4+ T cells. &#945;4&#946;7high CD4+ T cells are CCR5high and CXCR4low. We find that on these cells &#945;4&#946;7 appears in a complex with CD4. This is the first demonstration that these two receptors appear together in a complex on the surface of a CD4+ T cell. The delineation of the role of integrin &#945;4&#946;7 in HIV pathogenesis provides critical new information to understand the basic underlying mechanisms of HIV transmission and HIV-mediated immune dysfunction.